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available at www.sciencedirect.com
journal homepage: www.ejconline.com
SFOP OS94: A randomised trial comparing preoperative high-dose methotrexate plus doxorubicin to high-dose methotrexate plus etoposide and ifosfamide in osteosarcoma patients 5 Marie-Ce´cile Le Deleya,*, Jean-Marc Guinebretie`reb, Jean-Claude Gentetc, He´le`ne Pacquementd, Fabienne Pichone, Perrine Marec-Be´rardf, Natacha Entz-Werle´g, Claudine Schmitth, Laurence Brugie`resa, Daniel Vanela, Noe¨lle Dupou¨ya, Marie-Dominique Tabonei, Chantal Kalifaa, for the Socie´te´ Franc¸aise d’Oncologie Pe´diatrique (SFOP) a
Service de Biostatistique et d’Epide´miologie, Institut Gustave-Roussy, 39, rue Camille Desmoulins, 94805 Villejuif Cedex, France Centre Rene´-Huguenin, Saint Cloud, France c CHU La Timone, Marseille, France d Institut Curie, Paris, France e Centre Oscar Lambret, Lille, France f Centre Le´on-Be´rard, Lyon, France g CHU Hautepierre, Strasbourg, France h CHU Brabois, Nancy, France i CHU Trousseau, Paris, France b
A R T I C L E I N F O
A B S T R A C T
Article history:
The SFOP-OS94 randomised multi-centre trial was designed to determine whether preop-
Received 29 July 2006
erative chemotherapy regimen combining high-dose methotrexate courses and etopo-
Received in revised form
side-ifosfamide could improve the proportion of good histologic response (65% viable
28 September 2006
cells) compared to a regimen based on high-dose methotrexate and doxorubicin, in chil-
Accepted 6 October 2006
dren/adolescents with localised high-grade limb osteosarcoma. Postoperative chemother-
Available online 30 January 2007
apy was adapted to the histologic response.
5 Participating centres: University Hospital Centre La Timone, Marseille; Institut Curie, Paris; Centre Oscar-Lambret, Lille; Centre Le´onBe´rard, Lyon; University Hospital Trousseau, Paris; University Hospital Centre, Strasbourg; University Hospital Centre, Nancy; University Hospital Centre, Rouen; Centre Claudius-Regaud, Toulouse; University Hospital Centre, Montpellier; University Hospital Centre, Caen; University Hospital Centre, Rennes; University Hospital Centre, Grenoble; University Hospital Centre, Toulouse; University Hospital Centre, Tours; University Hospital Centre, Limoges; University Hospital Centre, Nantes; Centre Antoine-Lacassagne, Nice; University Hospital Centre, Besanc¸on; University Hospital Centre, Saint-Etienne; University Hospital Centre, Amiens; Centre Paul-Papin, Angers; University Hospital Centre, Dijon; University Hospital Centre, Bordeaux; University Hospital Centre, Clermont-Ferrand; University Hospital Centre, Reims; all in France; University Hospital Centre, Bruxelles, Belgium. * Corresponding author: Tel.: +33 1 42 11 54 44; fax: +33 1 42 11 52 58. E-mail address:
[email protected] (M.-C. Le Deley). 0959-8049/$ - see front matter 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.ejca.2006.10.023
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Keywords: Osteosarcoma Randomised trial Chemotherapy Etoposide-ifosfamide Doxorubicin Methotrexate Histologic response
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753
Overall, 234 patients were randomised between 1994 and 2001. There were 56% good responders in the etoposide-ifosfamide arm versus 39% in the doxorubicin arm (pvalue = 0.009). With a median follow-up of 77 months, the 5-year event-free survival of the entire population was 62%, slightly greater in the etoposide-ifosfamide arm than in the doxorubicin arm, but the difference was not significant (Hazard Ratio: HR = 0.71, 95%CI: 0.5–1.06, p-value = 0.09). Five-year overall survival of the entire population was 76%, similar in both arms (HR = 0.95, 95%CI: 0.6–1.6, p-value = 0.85). Toxicity was manageable with different acute toxicity profiles between treatment arms. No acute toxicity related death was reported. About 43% of the patients in the etoposide-ifosfamide arm were eventfree at 3 years without having received any doxorubicin or cisplatin, thus avoiding the risk of long-term cardio- and ototoxicity. Preliminary results of the study have been presented at the SIOP meeting, Brisbane, 2001 and at the ASCO meeting, Orlando, 2002. Audited by the French Competent Authority: AFSSAPS (Agence Franc¸aise de Se´curite´ SAnitaire des Produits de Sante´). Registered in the Clinical Trials.gov registry. Trial number: NCT00180908. 2007 Elsevier Ltd. All rights reserved.
1.
Introduction
Osteosarcomas are highly malignant tumours arising mainly in long bones. Neoadjuvant or adjuvant polychemotherapy has led to prognostic improvement compared to surgery alone, with relapse-free survival of 50% to 80%.1–5 Phase-2 trials have demonstrated the efficacy of high-dose methotrexate (HD-MTX),6 doxorubicin,7 cisplatin8 and more recently ifosfamide.9,10 Most of the current strategies deliver these three or four drugs preoperatively. In order to limit acute and long term toxicity of multi-drugs combination, we preferred another strategy combining, preoperatively, seven HD-MTX courses and two doxorubicin courses,11 the other drugs being reserved for salvage treatment of patients having a poor response to the initial treatment. Between 1992 and 1995, we conducted a phase-2 study combining etoposide (300 mg/m2) and ifosfamide (12 g/m2) in 27 heavily pre-treated osteosarcoma patients.12 Overall response rate was 48%. Other authors have reported a high response rate with this drug combination.13,14 The best combination of preoperative chemotherapy remains controversial and this prompted us to conduct a randomised trial in children and adolescents with osteosarcoma, testing the hypothesis that HD-MTX plus etoposide and ifosfamide might improve the number of good histologic responses compared to HD-MTX plus doxorubicin.
2.
Patients and methods
2.1.
Study design
A multi-centre randomised trial comparing efficacy and safety of two preoperative chemotherapy regimens, both based on HDMTX courses given alternately either with doxorubicin (standard treatment) or with etoposide-ifosfamide (new treatment).
2.2.
Eligibility criteria and pretreatment evaluation
Eligible patients were patients treated for a non metastatic limb osteosarcoma under 20 years of age. Other eligibility cri-
teria were biopsy-proven high-grade osteosarcoma excluding juxtacortical sarcoma and microcellular anaplastic sarcoma, no previous treatment, no contraindication to chemotherapy and no previous malignancy. Written informed consent was obtained from the parents and from patients aged 18 or above. The local ethics committees approved the protocol. The histological slides were centrally reviewed by one pathologist blinded to group assignment. In doubtful cases, initial imaging and biopsy specimens were reviewed by a panel of six radiology and bone pathology experts. The tumours were classified according to WHO criteria. Preliminary staging included plain radiography and MRI of the involved bone, bone scintigraphy, chest X-ray and CT-scan.
2.3.
Randomisation
Eligible patients were randomised by fax to the doxorubicin or etoposide-ifosfamide arm. A centralised randomisation software was used, with permuted blocks of size four and stratification according to centre category in three strata: the largest centre, all other large centres, all small centres.
2.4.
Treatment (Fig. 1)
2.4.1.
Preoperative chemotherapy
The doxorubicin arm consisted of seven courses of HD-MTX (12 g/m2) in 1.0 litre of 5% dextrose in water with 1 mEq/kg of sodium bicarbonate administered as a 4-h infusion. Oral rescue with leucovorin began 20 h after each methotrexate infusion at a dose of 15 mg up to a total of 11 doses given every 6 h. Hydration and alkalinisation were performed orally or intravenously (i.v.) to achieve urine output of 1.600 L/ m2 for the first 24 h and 2.000 L/m2 for the next 48 h with urine pH in excess of 7.0. Serum methotrexate levels and renal function were monitored daily. HD-MTX was administered on weeks 1, 2, 3, 6, 7, 10 and 11. Doxorubicin (70 mg/ m2) was administered as a 6-h continuous i.v. infusion on weeks 4 and 8.
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M M D
M M M D
M M
R G PR
Surgery
(MM M D)x3 +M MM
( E-I ) x 5
® M M E-I M
M M M E-I
®
:Randomisation
5
M M
9
R
+M MM
G PR
1
Surgery
( M M M E-I ) x 3
( P-D ) x 5
1 3
GR: Good Response
Weeks PR: Poor Response
M: High-dose Methotrexate, D: Doxorubicin, E-I: Etoposide-Ifosfamide, P-D: Cisplatinum-Doxorubicin Fig. 1 – Treatment plan.
The etoposide-ifosfamide arm consisted of seven courses of HD-MTX given on weeks 1, 2, 3, 7, 8, 12 and 13. Etoposide (75 mg/m2 i.v.) over 1 h in 250–500 mL saline serum and ifosfamide (3 g/m2/day i.v.) over 3 h in 250–500 mL saline serum were given daily for 4 days during weeks 4 and 9. Mesna (3.6 g/m2/day) was given as a continuous infusion for 4 days, with hydration up to 2.0 L/day.
2.4.2.
Surgery
Surgical excision of the primary tumour was planned during week 12 in the doxorubicin arm and week 14 in the etoposide-ifosfamide arm.
2.4.3.
Postoperative chemotherapy
Postoperative chemotherapy was adapted to the histologic response. Doxorubicin arm: good responders received 12 courses of HD-MTX and three courses of doxorubicin and poor responders received five courses of etoposide-ifosfamide. Etoposide-ifosfamide arm: good responders received 12 courses of HD-MTX and three courses of etoposide-ifosfamide and poor responders received five courses of cisplatin (120 mg/m2) and doxorubicin (70 mg/m2).
2.5.
Response assessment
The surgical specimen was assessed by the local pathologist blinded to group assignment. The histologic analysis of the tumour map was performed according to Huvos method.15 The mean percentage of residual viable cells was recorded. A good histologic response was defined as total or almost total necrosis (65% of viable cells). All the histological reports and tumour maps were reviewed by the senior author to validate the conclusion, blinded to group assignment.
2.6.
Follow-up
After completion of chemotherapy, chest X-rays were performed every 2 to 3 months for 3 years, every 4 months during the following 2 years and yearly thereafter. Bone scintigraphy was performed every 6 months during the first 3 years.
2.7.
Statistical considerations
2.7.1.
End point – sample size
The primary endpoint was a good histologic response after preoperative chemotherapy. Secondary endpoints were event-free survival (EFS), overall survival (OS) and toxicity. OS rates were estimated, using the Kaplan–Meier method, from the date of randomisation to death or the date of the last follow-up visit for patients last seen alive. EFS rates were estimated, using the same method, from randomisation to the time of first failure (loco-regional or distant relapse, second malignancy or death) or to the last follow-up visit for patients in first complete remission. Suspected local progression of the primary tumour before surgery was not considered as an event. Median follow-up was estimated using the inverse Kaplan–Meier method.16 Acute toxicity was assessed using the World Health Organisation (WHO) toxicity scale for children. The trial was designed to demonstrate a 20% absolute improvement from 50% to 70% in the rate of good histologic responses. A total of 206 patients was required to reach a power of 80% with a Type-I error of 5% (two-sided test, Casagrande and Pike). The investigators decided to include 226 patients given the planned interim analysis.
2.7.2.
Planned analysis
Analyses included all randomised patients, except those found not to have a malignant bone tumour at central histological review.
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The efficacy analyses were stratified on centre category, using logistic regression for the analysis of the response rate considering a poor histological response as a failure, and using the Cox model for survival analyses. Toxicity rates were compared using Chi-square tests. Secondary analyses used logistic regression to study variations in treatment effects according to major baseline characteristics (age, tumour size) and to centres. All reported pvalues are two-sided. Data were entered and checked with the PIGAS software17 and analysed with the SAS software (version 8.2; SAS Software, Cary, NC). One interim analysis was planned after inclusion and response assessment of 120 patients, using Pocock’s plan.18 Its result was seen only by the trial statistician.
3.
Results
3.1.
Accrual – study population
Between June 1994 and June 2001, 239 patients were included by 28 SFOP centres: 119 were allocated to the doxorubicin arm and 120 to the etoposide-ifosfamide arm. The histological review, performed centrally for 209 of the 239 randomised patients, led to the exclusion of five patients found not to have a malignant bone tumour. The study population therefore included 234 patients: 116 in the doxorubicin arm and 118 in the etoposide-ifosfamide arm (Fig. 2). Table 1 shows baseline patient characteristics. Five patients with a malignant bone tumour other than high-grade osteosarcoma and six patients with initial metastases before randomisation were randomised despite not being eligible; they are included in the analyses according to the intention-to-treat principle. The histologic response to chemotherapy, based on the surgical specimen, was assessed in the 234 patients.
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Median follow-up was 77 months for the whole population. All patients were followed up for more than 3 years, and up to a maximum of 10 years.
3.2.
Treatment
Chemotherapy was started at a median interval of 9 days after the biopsy (range: 1 to 55 days).
3.2.1.
Preoperative chemotherapy protocol
Among the 116 patients allocated to the doxorubicin arm, 86 (74%) received at least the seven HD-MTX courses and the two doxorubicin courses required by the protocol, 15 of them received one or two additional courses of HDMTX or doxorubicin. Fourteen patients (12%) received only six HD-MTX plus the two doxorubicin courses; these minor deviations were mainly due to the planned date of surgery. Sixteen patients (14%) received less than six courses of HDMTX and/or less than two doxorubicin courses because of toxicity or suspicion of tumour progression; they are considered as a major deviation from preoperative chemotherapy protocol. Among the 118 patients allocated to the etoposide-ifosfamide arm, 94 (80%) received at least the seven HD-MTX courses and the two etoposide-ifosfamide courses required by the protocol and 15 of them received one or two additional courses of HD-MTX. Twelve patients (10%) received only six HD-MTX plus the two etoposide-ifosfamide courses; these minor deviations were mainly due to the planned date of surgery. Twelve patients are considered as major deviation from preoperative chemotherapy protocol: 11 patients received less than six courses of HD-MTX or less than two courses of etoposide-ifosfamide because of toxicity or suspicion of tumour progression; an additional patient refused the allocated treatment and received the regimen administered in the doxorubicin arm.
486 patientsassessed for eligibility 247 patients not randomised • 188 did not meet eligibility criteria - 76 metastatic disease - 40 previously treated or initial surgery - 27 location other than limb -7 non high-grade osteosarcoma -39 miscellaneous reason • 33 Refused to participate • 26 Unknown reason
Follow-up
Analysis
Treatment Allocation
239 randomised patients 119 allocated to Doxorubicin Arm
120 allocated to Etoposide-Ifosfamide arm
3 patients excluded: no malignant bonetumour
116 patients analysed
2 patientsexcluded: no malignant bonetumour
118 patients analysed
16 major deviations from preoperative chemo.protocol 12 major deviations from preoperative chemo.protocol
116 evaluable
for the histological response for 3-year EFS and OS
755
118 evaluable
Fig. 2 – Trial profile.
for the histological response for 3-year EFS and OS
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Table 1 – Patient characteristics by treatment arm Characteristics
Treatment arm Doxorubicin (n = 116)
Age in years Median (range)
Etoposide-ifosfamide (n = 118)
Total (n = 234)
13.2 (3.1–19.5)
13.3 (5.5–19.3)
13.2 (3.1–19.5)
51%
61%
56%
Tumour location Lower limb, lower extremity femur Lower limb, upper extremity tibia Lower limb, other Upper limb
45% 20% 21% 14%
47% 23% 21% 9%
46% 21% 21% 12%
Disease extension at diagnosis Metastatic disease
2%
3%
3%
Tumour size P10 cm
50%
44%
47%
Alkaline phosphatase P2 · upper limit normal
23%
27%
25%
Histological subtype Common type Chondroblastic Fibroblastic Giant cells Telangiectatic Unclassified high-grade osteosarcoma Othera
67% 11% 11% 4% 6% 0% 1%
61% 21% 10% 2% 0% 2% 4%
64% 16% 11% 3% 3% 1% 2%
Sex Male
a Two juxta-cortical osteosarcomas: one per arm; two microcellular anaplastic osteosarcomas and one unclassified malignant bone tumour: all three in the etoposide-ifosfamide arm.
All patients were analysed according to the allocated treatment regardless of compliance.
arm regimen, 36 patients (73%) received four courses of cisplatin-doxorubicin or more.
3.2.2.
3.2.4. Toxicity 3.2.4.1. Chemotherapy-induced acute toxicity. Information on
Surgery
All patients underwent surgery 14.3 weeks (median) after the start of chemotherapy (inter-quartile range, 13 to 15 weeks, range 12 days to 27 weeks); this median time was 13.4 weeks in the doxorubicin arm and 15.0 weeks in the etoposideifosfamide arm. Conservative surgery was performed in 221 patients (94%) and amputation in 13 patients (6%), nine in the doxorubicin arm and four in the etoposide-ifosfamide arm (p-value = 0.16).
3.2.3.
Postoperative chemotherapy protocol
All but two patients received postoperative chemotherapy. To describe the postoperative chemotherapy regimen, we have excluded the six patients from the doxorubicin arm and the three from the etoposide-ifosfamide arm who received nonprotocol courses preoperatively. Among the 45 good responders after the doxorubicin arm regimen, 38 patients (84%) received three doxorubicin courses and nine HD-MTX courses or more. Among the 65 poor responders after the doxorubicin arm regimen, 61 patients (94%) received four courses of etoposide-ifosfamide or more. Among the 66 good responders after the etoposide-ifosfamide arm regimen, 56 patients (85%) received three courses of etoposide-ifosfamide and nine HD-MTX courses or more. Among the 49 poor responders after the etoposide-ifosfamide
acute toxicity was available for 98% of the 2027 preoperative protocol courses. No patient died of chemotherapy-induced acute toxicity. During preoperative chemotherapy, more patients experienced at least one episode of haematological toxicity in the etoposide-ifosfamide arm than in the doxorubicin arm (80% versus 65%, p-value = 0.01). Severe neutropenia (neutrophil count 10 · ULN, 66% versus 42%, p < 0.001). A transient reduction of left ventricular shortening fraction was reported in four patients of doxorubicin arm, without clinical signs. Two patients experienced neurotoxicity, one in each arm: one drowsiness during ifosfamide infusion
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and one seizure related to HD-MTX. Six patients experienced glomerular impairment, two in the etoposide-ifosfamide arm and four in the doxorubicin arm; five were related to HD-MTX and one to antibiotics. A transient tubular dysfunction was reported in two patients of the etoposide-ifosfamide arm. Haematuria was observed in four patients of the etoposideifosfamide arm and in one patient of the doxorubicin arm; all but one occurred after ifosfamide course. In all these 19 patients, the treatment could be continued without modification.
We did not observe any evidence of variation in this difference according to patient characteristics and the centre category; all interaction test p-values were above 0.45 (data not shown).
3.3.2.
4. Outcome
3.3.1.
Histologic response to preoperative chemotherapy
Event free and overall survival (Fig. 4)
The number of events (local or metastatic relapses, second tumours, deaths) was 54 in the doxorubicin arm and 41 in the etoposide-ifosfamide arm. The types of events are detailed in Table 2. The hazard ratio of events was 0.71 (95% CI: 0.5 to 1.06) in the etoposide-ifosfamide arm as compared to the doxorubicin arm. The difference was not statistically significant (p-value = 0.09). The 3-year EFS rates were 62% in the doxorubicin arm versus 69% in the etoposide-ifosfamide arm. No effect of randomised treatment on overall survival was observed (3-year OS, 84% and 83% respectively, hazard ratio = 0.95, 95% CI: 0.6 to 1.6, p-value = 0.85). In the whole population, EFS was 66% at 3 years and 62% at 5 years and OS was 83% and 76%, respectively. As shown in Fig. 5, EFS and OS were significantly higher in good responders than in poor responders (3-year EFS 79% and 54%, 3-year OS 93% and 75% respectively). In the doxorubicin arm, 3-year EFS was 82% in good responders and 49% in poor responders. In the etoposide-ifosfamide arm, 3-year EFS was 77% in good responders and 60% in poor responders.
3.2.4.2. Second malignancies. Six patients developed a second malignancy: a leiomyosarcoma of a limb 7.2 years after randomisation (n = 1), myelocytic acute leukaemia (n = 4) and myelodysplastic syndrome (n = 1), 1.4 to 2.7 years after randomisation. Four patients who developed a second malignancy had been treated in the doxorubicin arm (two good responders and two poor responders, including one who had received second-line treatment for an early postoperative relapse) and the two others in the etoposide-ifosfamide arm (both good responders). Four patients who developed haematological malignancy had received etoposide at a cumulative dose of 1500 mg/m2 (n = 3) and 2400 mg/m2 (n = 1); two of them had also received 140 mg/m2 of doxorubicin; the fifth patient had not received etoposide but 350 mg/m2 of doxorubicin. 3.3.
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Discussion
This randomised paediatric trial has confirmed the hypothesis that etoposide-ifosfamide plus HD-MTX leads to significantly more good histologic responses than doxorubicin plus HD-MTX (56% versus 39%). We chose the histologic response as the main endpoint to evaluate the efficacy of preoperative chemotherapy because it is strongly predictive of subsequent outcome2,4,5,19–23 and, in our treatment strategy,
Significantly more good responses were obtained in the etoposide-ifosfamide arm than in the doxorubicin arm: 56% versus 39% (p-value = 0.009). The results are similar when other cut-off values are considered: 64% versus 43% reported more than 90% necrosis (Fig. 3).
Good response
20% 30% Poor response
Percentage of viable cells
0% 5% 10%
40% 50% 60% 70% 80% 90%
100% -40%
-30%
-20%
-10%
Proportion of patients in the Doxorubicin arm (n=115)
0%
10%
20%
30%
40%
Proportion of patients in the Etoposide-Ifosfamide arm (n=116)
Fig. 3 – Histologic response by treatment arm. This information is available for 115/116 patients of doxorubicin arm and 116/ 118 patients of etoposide-ifosfamide arm. The mean percentage of residual viable cells was not recorded for three patients classified as poor responders.
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100%
80%
60%
40%
Overall Survival - Etoposide-Ifosfamide Arm
HR = 0.95, 95%CI, 0.58-1.6, p=.85
Overall Survival - Doxorubicin Arm 20%
Event-Free Survival - Etoposide-Ifosfamide Arm HR = 0.71, 95%CI, 0.47-1.06, p=.09
Event-Free Survival - Doxorubicin Arm 0% 0
1
2
3
4
5
6
7
8 Years
At risk 118
118
110
98
80
63
46
34
19
116
114
102
97
75
59
51
35
25
118
110
91
82
68
54
43
32
19
116
100
82
72
59
47
38
25
15
Fig. 4 – Overall (OS) and event-free (EFS) survival by treatment arm.
Table 2 – Outcome by treatment arm Outcome
Treatment arm Doxorubicin Estimates
Histologic response Good response Odds ratio of histologic failureb
45/116 39% 1c
Event-free survival (EFS) Type of first event Local relapse Metastatic relapse Local and metastatic relapse Second malignancy Toxic death
6 41 4 3d 0
Total number of events 3-year EFS 5-year EFS Hazard ratio of failureb
54 62% 58% 1c
Overall survival (OS) Cause of death Disease progression Second malignancy
29 2
Total number of deaths 3-year OS 5-year OS Hazard ratio of death
31 84% 75% 1c
(95%CI)a
(30–48%)
p-value Etoposide-ifosfamide
Estimates 66/118 56% 0.50
(95%CI)
(46–65%) (0.30–0.84)
0.009
(61–78%) (57–74%) (0.47–1.06)
0.09
(75–89%) (68–83%) (0.58–1.6)
0.85
4 32 3 2 0
(53–71%) (49–67%)
41 69% 66% 0.71
29 1
(76–89%) (66–82%)
30 83% 76% 0.95
a 95%CI: 95% confidence interval. b Adjusted on centre category. c Reference category. d Four patients of the Doxorubicin arm developed a second malignancy, but one haematological malignancy occurred after a relapse and thus is not a first event.
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759
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100%
80%
60%
40%
Overall Survival of Good Responders HR = 3.6, 95%CI, 2.0-6.5, p < 10-5
Overall Survival of Poor Responders 20%
Event-Free Survival of Good Responders HR = 2.8, 95%CI, 1.8-4.3, p < 10-5
Event-Free Survival of Poor Responders 0% 0
1
2
3
4
5
6
7
8 Years
At risk 111
111
107
103
83
123
121
105
92
72
66 58
111
108
96
88
73
59
123
102
77
66
54
44
38
27
46
33
18
45
33
22
36
25
13
51
Fig. 5 – Overall (OS) and event-free (EFS) survival of the entire population according to histologic response.
we used a salvage treatment postoperatively for poor responders. It is unlikely that the observed difference is related to the longer duration of preoperative chemotherapy since the number of courses is the same in both arms and the difference in median duration is only 1.6 weeks. The external validity of our trial is good: one can estimate that about 75 patients under 20 years of age are diagnosed with an osteosarcoma each year in France,24,25 leading to a total of 525 over 7 years; we have assessed for eligibility 486 of these patients (93%) and few patients with a non metastatic extremity osteosarcoma failed to enter into the trial. The control arm may presently be considered as suboptimal as compared to cisplatin-containing regimen currently used nowadays. However, when the trial was designed in 1993, the superiority of cisplatin-containing regimen was not clearly demonstrated.5 The 56% of total or near total necrosis and the 64% necrosis > 90% observed in the etoposide-ifosfamide arm, as well as the EFS, compare favourably with the results obtained with regimens combining HD-MTX, doxorubicin and cisplatin, with or without ifosfamide.1,2,20,22 In some of these publications, axial operable tumours and patients aged between 20 and 40 were also included but no difference in prognosis was reported between these categories of patients. EFS was slightly greater in the etoposide-ifosfamide arm than in the doxorubicin arm, but the difference was not significant (HR = 0.71, 95% CI: 0.5 to 1.06). If the observed reduction of 29% were true, this would be clinically significant. The power to detect an improvement in EFS was low in our study due to the small number of patients and the current followup. In the present trial, preoperative chemotherapy was based on a limited number of cytotoxic agents, the other drugs being reserved for postoperative treatment of poor responders. Salvage treatment of poor responders in the etoposide-
ifosfamide arm with five cisplatin-doxorubicin courses led to a 60% 3-year EFS rate, which compares favourably with EFS rates observed among poor responders in other trials.2,22,26 Overall, acute toxicity was manageable in this paediatric multi-centre study. Particularly, no acute toxicity related death was observed contrary to more intensive regimens.21,27 As expected, acute haematological toxicity was more frequent in the etoposide-ifosfamide arm. Unexpectedly, methotrexate-related hepatotoxicity was significantly less frequent in the etoposide-ifosfamide arm than in the doxorubicin arm. Long-term toxicity will be reported separately later, since data are presently immature. Patients receiving 60 g/m2 of ifosfamide should be carefully assessed for long-term renal function. At the present time, good responders who received HD-MTX and etoposide-ifosfamide courses alone are not exposed to the cardiotoxicity of doxorubicin nor to the ototoxicity of cisplatin. At 3 years of follow-up, they represent 43% of the patients in the etoposide-ifosfamide arm (56% good responders multiplied by 77% EFS at 3 years). The risk of leukaemia associated with etoposide and doxorubicin has been demonstrated.28 When the trial was initiated, the cumulative dose of etoposide equal to 1500 mg/m2 administered in this protocol was wrongly considered safe. In this study, one patient developed M5-AML with a t(9;11)(p21–22;q23) translocation involving the MLL gene, after having received HD-MTX plus 350 mg/m2 doxorubicin alone. An increased relative risk of second malignancy and particularly of leukaemia has been described after osteosarcoma, independently of treatment28–30 and could partly explain the high absolute leukaemia rate observed in this series. In conclusion, this trial has provided good evidence that the combination of etoposide-ifosfamide with HD-MTX led to a higher rate of good responses than doxorubicin. About 43% of the patients in the etoposide-ifosfamide arm were event free at 3 years and had not received any doxorubi-
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cin or cisplatin thus avoiding the risk of long-term cardio- and ototoxicity.
Source of funding The study was supported by the Association pour la Recherche sur le Cancer and by the Institut Gustave-Roussy, France. The funding sources had no involvement in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.
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gne, Nice, France; Emmanuel Plouvier, University Hospital Centre, Besanc¸on, France; Claire Berger, University Hospital Centre, Saint-Etienne, France; Eric Sariban, University Hospital Centre, Bruxelles, Belgique; Brigitte Pautard, University Hospital Centre, Amiens, France; Eric Gamelin, Centre Paul-Papin, France; Ge´rard Couillault, University Hospital Centre, Dijon, France; Yves Perel, University Hospital Centre, Bordeaux, France; Franc¸ois Demeocq, University Hospital Centre, Clermont-Ferrand, France; Martine Munzer, University Hospital Centre, Reims, France; for participating in the study.
Conflict of interest statement None declared.
Acknowledgements Authors’ contribution The authors contributed to – the conception and design of the trial as a member of the SFOP Osteosarcoma group (CK, JCG, HP, FP, PMB, MDT, NEW; CS, LB); – the inclusion of patients (CK, JCG, HP, FP, PMB, MDT, NEW; CS, LB); – the data management (ND); – the review of pathology data (JMG); – the review of radiological films (DV); – the analysis (MCLD) and interpretation of the data (CK, MCLD, LB, MDT); – the preparation of the manuscript (MCLD,CK, LB). All the authors critically reviewed earlier drafts and have read and approved the final version of the above mentioned manuscript. We are indebted – to all the children and parents who accepted to participate inthis study; – to Lorna Saint-Ange for editing; – to Chantal Rodary for designing the trial; – to Nicolas Bellon and Stefan Michiels for participating in the analysis; – to Catherine Hill for critical review of the manuscript; – to Annie Babin, University Hospital Centre, Strasbourg, Jean-Pierre Vannier, University Hospital Centre, Rouen, France; Herve´ Roche´, Centre Claudius-Regaud, Toulouse, France; Genevie`ve Margueritte, University Hospital Centre, Montpellier, France; Patrick Boutard, University Hospital Centre, Caen, France; Virginie Gandemer, University Hospital Centre, Rennes, France; Dominique Plantaz, University Hospital Centre, Grenoble, France; Herve´ Rubie, University Hospital Centre, Toulouse, France; Jean-Pierre Lamagne`re, University Hospital Centre, Tours, France; Lionel de Lumley, University Hospital Centre, Limoges, France; Franc¸oise Mechinaud, University Hospital Centre, Nantes, France; Antoine Thyss, Centre Antoine-Lacassa-
R E F E R E N C E S
1. Bacci G, Ferrari S, Bertoni F, et al. Long-term outcome for patients with nonmetastatic osteosarcoma of the extremity treated at the istituto ortopedico rizzoli according to the istituto ortopedico rizzoli/osteosarcoma-2 protocol: an updated report. J Clin Oncol 2000;18(24):4016–27. 2. Bielack SS, Kempf-Bielack B, Delling G, et al. Prognostic factors in high-grade osteosarcoma of the extremities or trunk: an analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols. J Clin Oncol 2002;20(3):776–90. 3. Link MP, Goorin AM, Miser AW, et al. The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J Med 1986;314(25):1600–6. 4. Rosen G, Caparros B, Huvos AG, et al. Preoperative chemotherapy for osteogenic sarcoma: selection of postoperative adjuvant chemotherapy based on the response of the primary tumor to preoperative chemotherapy. Cancer 1982;49(6):1221–30. 5. Winkler K, Beron G, Kotz R, et al. Neoadjuvant chemotherapy for osteogenic sarcoma: results of a Cooperative German/ Austrian study. J Clin Oncol 1984;2(6):617–24. 6. Jaffe N, Paed D, Farber S, et al. Favorable response of metastatic osteogenic sarcoma to pulse high-dose methotrexate with citrovorum rescue and radiation therapy. Cancer 1973;31(6):1367–73. 7. Cortes EP, Holland JF, Wang JJ, Sinks LF. Doxorubicin in disseminated osteosarcoma. JAMA 1972;221(10):1132–8. 8. Ochs JJ, Freeman AI, Douglass Jr HO. et al. cisDichlorodiammineplatinum (II) in advanced osteogenic sarcoma. Cancer Treat Rep 1978;62(2):239–45. 9. Harris MB, Cantor AB, Goorin AM, et al. Treatment of osteosarcoma with ifosfamide: comparison of response in pediatric patients with recurrent disease versus patients previously untreated: a Pediatric Oncology Group study. Med Pediatr Oncol. 1995;24(2):87–92. 10. Marti C, Kroner T, Remagen W, et al. High-dose ifosfamide in advanced osteosarcoma. Cancer Treat Rep 1985;69(1):115–7. 11. Kalifa C, Brunat-Mentigny M, Pacquement H, et al. Treatment of Osteosarcoma (OS) with an Intensive Chemotherapy Regimen (OS87 protocol). Med Pediatr Oncol 1996;27(4):251. 12. Gentet JC, Brunat-Mentigny M, Demaille MC, et al. Ifosfamide and etoposide in childhood osteosarcoma. A phase II study of the French Society of Paediatric Oncology. Eur J Cancer 1997;33(2):232–7. 13. Goorin AM, Harris MB, Bernstein M, et al. Phase II/III trial of etoposide and high-dose ifosfamide in newly diagnosed metastatic osteosarcoma: a pediatric oncology group trial. J Clin Oncol 2002;20(2):426–33.
EUROPEAN JOURNAL OF CANCER
14. Miser JS, Kinsella TJ, Triche TJ, et al. Ifosfamide with mesna uroprotection and etoposide: an effective regimen in the treatment of recurrent sarcomas and other tumors of children and young adults. J Clin Oncol 1987;5(8):1191–8. 15. Huvos AG, Rosen G, Marcove RC. Primary osteogenic sarcoma: pathologic aspects in 20 patients after treatment with chemotherapy en bloc resection, and prosthetic bone replacement. Arch Pathol Lab Med 1977;101(1):14–8. 16. Rothman KJ. Estimation of confidence limits for the cumulative probability of survival in life table analysis. J Chronic Dis 1978;31(8):557–60. 17. Wartelle M, Kramar A, Jan P, Kruger D. PIGAS: An interactive statistical database management system. Proceedings of the Second National Workshop on Statistical Database Management, 1983. 18. Pocock SJ. Size of cancer clinical trials and stopping rules. Br J Cancer 1978;38(6):757–66. 19. Souhami RL, Craft AW, Van der Eijken JW, et al. Randomised trial of two regimens of chemotherapy in operable osteosarcoma: a study of the European Osteosarcoma Intergroup. Lancet 1997;350(9082):911–7. 20. Meyers PA, Gorlick R, Heller G, et al. Intensification of preoperative chemotherapy for osteogenic sarcoma: results of the Memorial Sloan-Kettering (T12) protocol. J Clin Oncol 1998;16(7):2452–8. 21. Meyers PA, Schwartz CL, Krailo M, et al. Osteosarcoma: a randomized, prospective trial of the addition of ifosfamide and/or muramyl tripeptide to cisplatin, doxorubicin, and high-dose methotrexate. J Clin Oncol 2005;23(9):2004–11. 22. Smeland S, Muller C, Alvegard TA, et al. Scandinavian Sarcoma Group Osteosarcoma Study SSG VIII: prognostic factors for outcome and the role of replacement salvage
23.
24.
25.
26.
27.
28.
29.
30.
4 3 ( 2 0 0 7 ) 7 5 2 –7 6 1
761
chemotherapy for poor histological responders. Eur J Cancer 2003;39(4):488–94. Winkler K, Beron G, Delling G, et al. Neoadjuvant chemotherapy of osteosarcoma: results of a randomized cooperative trial (COSS-82) with salvage chemotherapy based on histological tumor response. J Clin Oncol 1988;6(2):329–37. Desandes E, Lacour B, Sommelet D, et al. Cancer incidence among adolescents in France. Pediatr Blood Cancer 2004;43(7):742–8. Desandes E, Clavel J, Berger C, et al. Cancer incidence among children in France, 1990-1999. Pediatr Blood Cancer 2004;43(7):749–57. Bacci G, Forni C, Ferrari S, et al. Neoadjuvant chemotherapy for osteosarcoma of the extremity: intensification of preoperative treatment does not increase the rate of good histologic response to the primary tumor or improve the final outcome. J Pediatr Hematol Oncol 2003;25(11):845–53. Ferrari S, Smeland S, Mercuri M, et al. Neoadjuvant chemotherapy with high-dose ifosfamide, high-dose methotrexate, cisplatin, and doxorubicin for patients with localized osteosarcoma of the extremity: A Joint Study by the Italian and Scandinavian Sarcoma Groups. J Clin Oncol 2005. Le Deley MC, Leblanc T, Shamsaldin A, et al. Risk of secondary leukemia after a solid tumor in childhood according to the dose of epipodophyllotoxins and anthracyclines: a case-control study by the Societe Francaise d’Oncologie Pediatrique. J Clin Oncol 2003;21(6):1074–81. Pratt CB, Meyer WH, Luo X, et al. Second malignant neoplasms occuring in survivors of osteosarcoma. Cancer 1997;80(5):960–5. Ferrari C, Bohling T, Benassi MS, et al. Secondary tumors in bone sarcomas after treatment with chemotherapy. Cancer Detect Prev 1999;23(5):368–74.
